2973

Medulloblastoma, a highly malignant embryonal tumor of the cerebellum, is frequently disseminated throughout the central nervous system by the time of diagnosis. The highly metastatic medulloblastoma represents approximately 25% of all pediatric intracranial neoplasms. Conventional therapeutic approaches have not reduced the high mortality associated with metastatic medulloblastoma and little is known regarding the molecular mechanisms that promote tumor invasion. Matrix metalloproteinases (MMPs) comprise a family of zinc-dependent enzymes, which degrade various components of the extracellular matrix (ECM) and play an important role in facilitating neoplastic cell invasion and metastasis. Medulloblastomas have been shown to display distinct regional MMP expression and acquisition MMP-2 activity is temporally associated with the increased migration and invasiveness of cancer cells. Here, we have studied the effect of small interfering RNA (siRNA) targeting MMP-2 gene expression on the tumorigenicity of a medulloblastoma cell line. Infection of medulloblastoma cells by Ad-MMP-2 Si reduced MMP-2 enzyme activity and intracellular MMP-2 expression as determined by gelatinase activity and immunohistochemical analysis. In addition, the invasion of cells through matrigel was inhibited in a dose-dependent manner when compared to the controls. Furthermore, intratumoral injection of Ad-MMP-2 Si diminished pre-established tumor growth in nude mice. In conclusion, these data demonstrate that RNAi-mediated MMP-2 downregulation presents a potential therapeutic approach for gene therapy in medulloblastomas.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]